The present invention relates to the separation of chiral compounds and a unique polymer film or powder and process using these materials to perform this separation. In particular, the invention relates to separation of enantiomers of pharmaceutical compounds or amino acids.
Enantioseparations are becoming increasingly important because the U.S. Food and Drug Administration has declared that if a drug is chiral, the biological effects of both enantiomers must be determined; Stinson, S. C. "Chiral Drugs", Chem. Eng News 1995, 73, 41; Collins, A. N., Sheldrake, G. N. & Crosby, J. "Chirality in Industry" (Wiley & Sons, Chichester), 1992.) Many procedures for resolution of D, L-amino acids have been documented (Turk, J., Panse, G. T. Marshall, G. R." Studies with a-methyl amino acid resolution and amino protection", J. Org. Chem. 1975, 40, 953; Meijer, E. M., Boesten, W. H. J., Schomaker, H. E., Van Balken, J. A. M. "Use of biocatalyst in the industrial production of specialty chemicals" Biocatalysis in organic synthesis. (Tramper, J., Van Der Plas, H. C., Linko, P., Eds). Amsterdam: Elsevier, 1985,135; Schutt, H., Schmidt-Kastner, G., Arens, A., Preiss, M. "Preparation of optically active D-arylglycines for use as side chains for semisynthetic penicillins and cephalsoporins using immobilized subtilisins in two-phase systems" Biotech. Bioeng. 1985,27, 420; Moller, A., Syldatk, C., Schulze, M., Wagner, F. "Stereo- and substrate-specificity of a D-hydantoinase and a D-N-carbamyl-amino acid amidohydrolase of Arthrobacter crystallopoietes AM2," Enzyme Microb. Technol. 10:618-625; Wong, C. H., Chen, S. T., Hennen, W. J., Wang, Y. F., Liu, J. L. -C., Pantoliano, M. W., Whitlow, M., Bryan, P. N. "Enzymes in organic synthesis: Use of subtilisin and a highly stable mutant derived form multiple site specific mutations", J. Am. Chem. Soc. 1990, 112, 945; Sato, T. Tosa, T. "Optical resolution of racemic amino acids by aminoacylase", Industrial Application of Immobilized Biocatalysts.(Tanaka, A., Tosa, T., Kobayashi, T., Eds.) Marcel Dekker, New York: 1993,3).
D-amino acids along with unnatural amino acids have found extensive application as antibiotic peptides, and as synthetic peptides with enhanced hormonal or neural activity. (Folkers, K., Hoerig, J., Rosell, S., Bjoerkroth, U. "Chemical design of antagonists of substance P: Acta Physiol. Scand. 1981, 111, 505; Manavalan, P., Momany, F. A. "Conformational studies on the enkephalin releasing peptides, tyr-arg and tyr-d-arg", Biochem. Biophys. Res. Commun. 1982, 105(3), 847: Blanc, J. P., Kaiser, E. T. "Biological and physical properties of a b-endorphin analog containing only D-amino acids in the amphophilic helical segment 13-31", J. Biol. Chem. 259(15): 9549-9556. Most of these unnatural amino acids are unavailable through fermentation. Resolution is an effective means of producing optically pure unnatural amino acids. Traditionally, racemate amino acids can be resolved by entrainment with enzymes or bacteria, or by using chiral stationary phase liquid chromatography (LC) or high performance liquid chromatography (HPLC). These methods are limited by the economic costs as well as the difficulty of scale up to commercially viable processes. Liquid membranes have also been reported in the literature to be used for enantioseparations of racemate amino acids but so far have shown poor separating abilities.
Additionally, certain pharmaceutical compounds are known to provide effective treatment against disease states or to ameliorate medical conditions. These compounds often occur as a chiral mixture where one enantiomeric form is more effective for its intended purpose than other enantiomeric forms of the same compounds. In fact, certain enantiomeric forms may act to counteract the beneficial effects of other enantiomeric forms. Therefore, it is highly beneficial to be able to separate out and collect the most effective forms of enantiomeric compounds.
There presently are no readily universal techniques or materials which are available for the general separation of chiral compounds. As indicated above, there is a need for a process and materials which will allow a broad range of different chiral materials to be consistently separated in an economical, quantitative and high purity manner.